The nervous and immune systems of man are made up of complex networks of cells that monitor specific body signals and respond appropriately. While effects of the brain on the immune system are well characterized, modulation of brain cell function by immunocompetent cells, especially under conditions of brain injury, is not well characterized. These studies seek to identify and characterize endogenous inflammatory pathways that both increase neuronal resistance to brain injury, and increase synaptic recovery following brain injury. Additionally, pharmacological agents that could mimic these neuroprotective pathways will be evaluated. This proposal, therefore, will determine the role of microglial cells, brain resident immunologic cells, in the development of brain injury. Using a well characterized in slice culture model that preserves the physiological, three-dimensional architecture of the brain, this propose will employ well-characterized pharmacological agents to modulate microglial activation in models of excitotoxicity (i.e., seizure-induced damage), anoxia (i.e., stroke), and amyloid- dependent (i.e., Alzheimer s like pathology). Specific Aim 1 tests the general hypothesis that activation of microglial cells is neuroprotective in these models. Specific Aim 2 tests the hypothesis that microglia protect neuronal systems by channeling death pathways towards apoptosis rather than necrosis, and then isolating/removing the apoptotic cells. Specific Aim 3 tests a hypothesis that microglial activation increases both neuronal to injury and neuronal recovery following injury by selective targeting and removal of white matter (myelin) debris. It is especially important to understand the specific contributions of inflammatory mediators to brain injury because under most clinical settings the first priority is to stop immune and inflammatory processes. The possibility therefore exists that new pharmacological interventions could be devised based on studies such as these that lead to increased efficacy in the treatment and therapeutic recovery of victims of traumatic spinal or brain injury.